1,2,5,6-tetrahydropyridine oxime derivatives

ABSTRACT

Compounds of formula (I) or a pharmaceutically acceptable salt thereof: ##STR1## wherein R 1  represents a 1,2,5,6-tetrahydropyridin-3-yl group N-substituted by R 10  wherein R 10  represents OH; a group hydrolysable in vivo to OH or hydrogen; C 1-8  alkoxy; C 2-8  alkenyloxy; C 2-8  alkynyloxy; C 3-8  cycloalkyloxy; or COR 13  wherein R 13  represents hydrogen, C 1-8  alkyl, phenyl or phenyl C 1-4  alkyl; in which any phenyl moiety is optionally substituted by up to 3 substituents independently selected from C 1-6  alkoxy, C 1-6  alkyl, halo, C 1-6  alkoxycarbonyl, cyano, C 1-6  alkylthio or C 1-6  alkylsulphonyl; enhance acetylcholine function via an action at muscarinic receptors within the central nervous system and are therefore of potential use in the treatment and/or prophylaxis of dementia in mammals.

This invention relates to compounds having pharmaceutical activity, to aprocess for their preparation and their use as pharmaceuticals.

EP-0288394, U.S. Pat. Nos. 4,921,868 and 4,902,699 disclose certain1,2,5,6-tetrahydropyridine 3-ketoxime and -3-aldoxime derivatives havingcholinomimetic activity.

A novel group of compounds has now been discovered which enhanceacetylcholine function via an action at muscarinic receptors within thecentral nervous system and are therefore of potential use in thetreatment and/or prophylaxis of dementia in mammals.

According to the present invention, there is provided a compound offormula (I) or a pharmaceutically acceptable salt thereof: ##STR2##wherein R₁ represents a 1,2,5,6-tetrahydropyridin-3-yl groupN-substituted by R₁₀ wherein R₁₀ represents OH; a group hydrolysable invivo to OH or hydrogen; C₁₋₈ alkoxy; C₂₋₈ alkenyloxy; C₂₋₈ alkynyloxy;C₃₋₈ cycloalkyloxy; or COR₁₃ wherein R₁₃ represents hydrogen, C₁₋₈alkyl, phenyl or phenyl C₁₋₄ alkyl; in which any phenyl moiety isoptionally substituted by up to 3 substitutents independently selectedfrom C₁₋₆ alkoxy, C₁₋₆ alkyl, halo, C₁₋₆ alkoxycarbonyl, cyano, C₁₋₆alkylthio or C₁₋₆ alkylsulphonyl;

R₂ is a group OR₄, where R₄ is C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, agroup OCOR₅ where R₅ is hydrogen or R₄, or a group NHR₆ or NR₇ R₈ whereR₆, R₇ and R₈ are independently C₁₋₂ alkyl; and

R₃ is chloro, fluoro, bromo, C₁₋₃ alkyl substituted by one, two or threehalogen atoms, or R₃ is a group (CH₂)_(n) R₉ where R₉ is --CN, --OH,--OCH₃, --SH or --SCH₃ and n is O or 1, with the proviso that when n isO, R₉ is not --OH or --SH.

The term halogen includes bromine, chlorine, fluorine and iodine. R₃halo is preferably fluorine. Halo in R₁₀ is preferably chlorine.

Compounds of formula (I) are capable of existing in a number ofstereoisomeric forms including geometric isomers such as syn and antiand, for certain compounds, enantiomers. The invention extends to eachof these stereoisomeric forms, and to mixtures thereof (includingracemates). The different stereoisomeric forms may be separated one fromthe other by the usual methods, or any given isomer may be obtained bystereospecific or asymmetric synthesis.

The compounds of formula (I) can form acid addition salts with acids,such as the conventional pharmaceutically acceptable acids, for examplehydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic,citric, lactic, mandelic, tartaric, oxalic and methanesulphonic.

The term pharmaceutically acceptable salt encompasses solvates andhydrates. Thus where compounds of formula (I) or pharmaceuticallyacceptable salts thereof form solvates or hydrates, these also form anaspect of the invention.

Examples of suitable groups hydrolysable in vivo to OH include C₁₋₈alkanoyloxy, C₁₋₈ alkoxycarbonyloxy, phenyl C₁₋₄ alkanoyloxy and--OCONHR₁₂ wherein R₁₂ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₃₋₈ cycloalkyl, phenyl or phenyl C₁₋₄ alkyl, in which anyphenyl moiety is optionally substituted as aforesaid.

Examples of suitable groups hydrolysable in vivo to hydrogen includeCOOZ in which Z represents C₁₋₁₈ alkyl optionally substituted by triC₁₋₆ alkylsilyl or C₁₋₆ alkylsulphonyl, C₂₋₁₈ alkenyl, C₂₋₁₈ alkynyl,C₃₋₈ cycloalkyl C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, phenyl or phenyl C₁₋₄alkyl; in which any phenyl moiety is optionally substituted asaforesaid.

In a preferred aspect, therefore, R₁₀ represents COOZ in which Zrepresents C₁₋₁₈ alkyl optionally substituted by tri C₁₋₆ alkylsilyl orC₁₋₆ alkylsulphonyl, C₂₋₁₈ alkenyl, C₂₋₁₈ alkynyl, C₃₋₈ cycloalkyl C₁₋₄alkyl, C₃₋₁₀ cycloalkyl, phenyl or phenyl C₁₋₄ alkyl; OR₁₁ wherein R₁₁represents hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈cycloalkyl, C₁₋₈ alkanoyl, C₁₋₈ alkoxycarbonyl, phenyl C₁₋₄ alkanoyl orCONHR₁₂ wherein R₁₂ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₈ cycloalkyl, phenyl or phenyl C₁₋₄ alkyl; or COR₁₃ wherein R₁₃represents hydrogen, C₁₋₈ alkyl, phenyl or phenyl C₁₋₄ alkyl; in whichany phenyl moiety is optionally substituted as aforesaid.

Aliphatic Z in R₁₀ preferably contains up to 8 carbon atoms, morepreferably up to 6.

Aliphatic R₁₁ and R₁₃ groups in R₁₀ preferably contain up to 4 carbonatoms. Phenylalkyl or phenylalkanoyl groups in R₁₀ are preferablyphenyl-C₁₋₂ alkyl or -C₁₋₂ alkanoyl.

Substituents on phenyl in R₁₀ preferably contain up to 3 carbon atoms.

Examples of R₁₀ groups include COOZ in which Z is methyl, ethyl,n-propyl, iso-propyl, n-butyl, t-butyl, allyl, benzyl, phenethyl,phenyl, 4-chlorophenyl, 4-isopropylphenyl, 3,4-dimethoxyphenyl,adamantyl, 2-methylsulphonylethyl or 2-trimethylsilylethyl, and OR₁₁where R₁₁ is hydrogen, methyl, ethyl, acetyl, pivaloyl, ethoxycarbonyl,benzoyl or CONHR₁₂ where R₁₂ is ethyl, n-propyl, iso-propyl, n-butyl,phenyl, 4-chlorophenyl, 4-isopropylphenyl, 4-methoxyphenyl,3-chlorophenyl, 3-methoxyphenyl, 3,4-dichlorophenyl or 1-phenyl-1-ethyl.

Preferred examples of R₁₀ include hydroxy, phenyloxycarbonyl,4-methoxyphenyloxycarbonyl, 3,4-dimethoxyphenyloxycarbonyl, acetoxy,propylaminocarbonyloxy and phenylaminocarbonyloxy.

The groups R₄ and R₅ in R₂ are preferably selected from methyl, ethyl,allyl and propargyl. R₆, R₇ and R₈ are preferably methyl. Suitablevalues for R₂ include methoxy, ethoxy, allyloxy, propargyloxy, acetoxyand dimethylamino, preferably methoxy.

Suitable examples for R₃ include methoxy, chloro, fluoro and bromo andwhen R₃ is a group (CH₂)_(n) R₉ and n is O, an example of R₉ is --CN.When n is 1, an example of R₉ is CN.

The invention also provides a process for the preparation of a compoundof formula (I), or a pharmaceutically acceptable salt thereof, whichprocess comprises:

(a) reacting a compound of formula (II): ##STR3## with a compound offormula (III):

    R.sub.2 '--NH.sub.2                                        (III)

wherein R₁ ' represents R₁ or a group convertible thereto, R₂ 'represents R₂ or hydroxy, and R₃ ' represents R₃ or a group convertiblethereto, converting R₂ ' to R₂ when hydroxy, converting R₁ ' and R₃ 'when other than R₁ and R₃ to R₁ and R₃, wherein R₁, R₂ and R₃ are asdefined in formula (I), and thereafter optionally forming apharmaceutically acceptable salt;

(b) reacting a compound of formula (IV): ##STR4## with a compound offormula (V):

    M--R.sub.3 '                                               (V)

capable of generating an R₃ ' nucleophile wherein R₁ ' represents R₁ ora group convertible thereto, R₃ ' represents R₃ or a group convertiblethereto, converting R₁ ' and R₃ ' when other than R₁ and R₃ to R₁ andR₃, wherein R₁, R₂ and R₃ are as defined in formula (I), and thereafteroptionally forming a pharmaceutically acceptable salt;

(c) reacting a compound of formula (IVa): ##STR5## wherein R₁ ' is R₁ ora group convertible thereto and wherein R₁ and R₂ are as defined informula (I), with a chlorinating, brominating or fluorinating agent,converting R₁ ' when other than R₁ to R₁, optionally converting R₃ whenchloro or bromo to other R₃, wherein R₃ is as defined in formula (I) andthereafter optionally forming a pharmaceutically acceptable salt;

(d) the nitrosation of a compound of formula (IVb): ##STR6## wherein R₁' and R₃ ' are as defined in formula (II), and thereafter converting theresulting ═NOH group to ═NR₂ wherein R₂ is as defined in formula (I),converting R₁ ' and R₃ ' when other than R₁ and R₃ to R₁ and R₃ andoptionally forming a pharmaceutically acceptable salt; or

(e) reacting a compound of formula (IVc) ##STR7## wherein R₁ ' and R₃ 'represent R₁ and R₃ as defined in formula (I) or groups convertiblethereto, to convert the hydroxy group to R₂ as defined in formula (I),and thereafter converting R₁ ' and R₃ ' when other than R₁ and R₃ to R₁and R₃ and optionally forming a pharmaceutically acceptable salt.

It will be appreciated that compounds of formula (IV) are identical tocompounds of formula (I) in which R₁ ' is R₁ and R₃ is chloro or bromo,and as such are themselves part of the invention.

The reaction between the compounds of formulae (II) and (III) ispreferably carried out in a hydroxylic solvent such as methanol orethanol, at ambient temperature, or where appropriate, in an inertsolvent such as toluene at elevated temperature.

Where R₂ in compounds of formula (I) is a group OR₄, NHR₆ or NR₇ R₈, acompound of formula (II) is conveniently reacted with a compound offormula (III) in which R₂ ' is R₂.

Where R₂ in compounds of formula (I) is a group OCOR₅, a compound offormula (II) may be reacted with the compound of formula (III) in whichR₂ ' is hydroxy, with subsequent acylation of the resulting oxime offormula (IVc) by treatment with a suitable acylating agent such as anacyl halide, for example acetyl chloride.

The reaction between compounds of formulae (IV) and (V) may be carriedout under standard conditions for the displacement of halogen by anucleophile.

Where R₃ in compounds of formula (I) is fluoro, the residue M issuitably caesium, the caesium fluoride reagent being supported oncalcium fluoride in dimethylformamide at elevated temperature for aprolonged period.

The nitrosation of a compound of formula (IVb) is preferably carried outusing t-butyl nitrite and a base such as sodium ethoxide or, morepreferably, potassium t-butoxide, and R₃ ' is preferably an electronwithdrawing group other than halo, such as CN. The resulting ═NOH groupin the oxime of formula (IVc) may be converted to ═NR₂ by conventionalroutes such as acylation as described above or alkylation with analkylating agent such as methyltosylate or an alkyl halide, for examplemethyl iodide. It will be appreciated that R₃ ' is preferably other thanhalo, such as CN.

The product of the reaction of compounds of formulae (II) and (III) andformulae (IV) and (V) and the nitrosation of the compound of formula(IVb) is a compound of formula (IIa): ##STR8## wherein R₂ ' representsR₂ or hydroxy and R₁ ' and R₃ ' represent R₁ and R₃ or a groupsconvertible thereto, and R₁, R₂ and R₃ are as defined in formula (I) .

It will be appreciated that the reaction of compounds of formula (IVa)with a chlorinating, brominating or fluorinating agent will yieldcompounds of formula (I) wherein R₃ is chloro, bromo or fluoro. Suitablechlorinating agents include phosphorus pentachloride which undergoesreaction in nitromethane at reduced temperature, for example 0° C., anddichlorontriphenylphosphine or carbon tetrachloride/triphenyl phosphinewhich undergoes reaction in acetonitrile at elevated temperature, forexample at the boiling point of the solvent. Suitable brominating agentsinclude dibromotriphenylphosphine or carbontetrabromide/triphenylphosphine which undergoes reaction in acetonitrileat elevated temperature, for example at the boiling point of thesolvent. Suitable fluorinating agents include diethylaminosulphurtrifluoride (DAST) which also undergoes reaction in acetonitrile atelevated temperature.

Conversion of the resulting R₃ halogen group when chloro or bromo toother R₃ groups may be effected by reaction variant (b) above.

Examples of groups R₁ ' convertible to R₁ include pyridin-3-yl,1-oxopyridinium-3-yl and 1-alkyl-pyridinium-3-yl. A pyridin-3-yl groupmay be converted to a 1-substituted pyridinium-3-yl group by treatmentwith an alkylating agent such as a halide derivative e.g. methyl iodideand the pyridinium moiety converted to the required tetrahydropyridinemoiety by reduction with a suitable reducing agent such as sodiumborohydride. Dealkylation may be effected by treatment with a suitablechloroformate ester reagent. For example, demethylation may be effectedwith α-chloroethylchloroformate (R. A. Olofson et. al., J. Org. Chem.1984 49 2081) in dichloromethane followed by methanol.

Certain intermediates of formula (IIa) wherein R₁ ' is not R₁ when R₂ 'is R₂ and R₃ ' is R₃ and salts thereof, also form part of the invention,in particular compounds of formula (IIa) wherein R₁ ' is1-oxopyridinium-3-yl.

Introduction of R₁₀ ═COOZ groups may be effected by treatment of the NHcompound with an appropriate chloroformate ester such as 4-methoxyphenylchloroformate in dry solvent such as toluene in the presence of basesuch as triethylamine at ambient temperature.

Introduction of R₁₀ ═COR₁₃ groups may be effected by acylation of the NHcompound with an appropriate acyl halide or anhydride.

Introduction of R₁₀ ═OR₁₁ groups is preferably effected via R₁₀═hydroxy. The unsubstituted tetrahydropyridine moiety may be treatedwith disodium hydrogen phosphate and benzoyl peroxide to give theN-benzoyloxy derivative which may then be treated with base such as analkali metal alkoxide e.g. sodium methoxide to yield the N-hydroxyderivative.

Alternatively, a pyridin-3-yl group may be converted to the N-oxide bytreatment with a suitable oxidising agent such as m-chloro perbenzoicacid and the resulting 1-oxopyridinium group reduced to the1-hydroxytetrahydropyridine moiety by reduction with a suitable reducingagent such as sodium borohydride.

The R₁₀ ═hydroxy group may then be derivatised by standard methods, forexample by introduction of R₁₁ ═acyl or alkoxycarbonyl using theappropriate halo derivative R₁₁ -hal in an inert solvent such astetrahydrofuran. R₁₁ groups CONHR₁₂ may be introduced by reaction of theR₁₀ ═hydroxy group with the appropriate isocyanate in toluene at ambienttemperature. R₁₁ ═alkyl may be introduced by reaction of the R₁₀ hydroxycompound with sodium hydride followed by treatment with an alkylatingagent such as an alkyl halide.

Compounds of formula (II) and compounds of formulae (IV) and (IVa) maybe prepared from an intermediate compound of formula (VI): ##STR9## inwhich L is a leaving group such as chloro, bromo, C₁₋₄ alkoxy orN-methoxy-N-methylamino and R₁ ' is as defined in formula (II). Acompound of formula (VI) in which L is preferably chloro or bromo may bereacted with N,O-dimethylhydroxylamine and the resultingN-methoxy-N-methylcarboxamide derivative or a carboxy ester derivativereacted with a compound of formula (V), suitably an organolithium orGrignard reagent, to provide a compound of formula (II). For example thereaction product of acetonitrile and lithium diisopropylamide will yielda compound of formula (II) where R₃ is CH₂ CN. It will be appreciatedthat the resulting compound of formula (II) will be in the form of thelithium enolate salt.

A compound of formula (VI) may alternatively be reacted with a compoundof formula (III) wherein R₂ ' is OR₄, in chloroform or acetonitrile or amixture as solvent, in the presence of a base such as pyridine ortriethylamine, and the resulting derivative of formula (IVa) treatedwith a chlorinating or brominating agent to provide a compound offormula (IV) in which R₂ ' is OR₄.

Novel compounds of formulae (II), (IV), (IVa), (IVb) and (IVc) also formpart of the invention.

Compounds of formula (VI) and certain compounds of formula (II) may beprepared by conventional routes for preparing carboxylic acidderivatives from commercially available starting materials.

Thus, for example, compounds of formula (II) where R₁ ' is pyridyl andR₃ ' is C₁₋₃ alkyl substituted as defined or CH₂ R₉ may be prepared bytreatment of 3-bromopyridine with n-butyllithium followed by reactionwith the appropriate α-substituted N-methoxy-N-methylacetamide.

The acetamide reagent may be prepared by reacting N,O-dimethylhydroxylamine with the corresponding α-substituted acetic acid or anappropriate reactive derivative thereof in the presence of base such astriethylamine or 2,6-dimethylpyridine.

The compound of formula (IVb) wherein R₁ ' is pyridyl and R₃ ' is cyanois commercially available.

Compounds of formula (III) are known compounds or may be prepared byanalogous methods to those for preparing known compounds. Certaincompounds of formula (III) are commercially available.

The different stereoisomeric forms of compounds of formula (I) may beseparated one from the other by the usual methods, for example usingchromatographic methods. Enantiomers may be separated using chiralresolving agents or chiral chromatography, or any given isomer may beobtained by stereospecific or asymmetric synthesis.

Pharmaceutically acceptable salts of the compounds of formula (I) may beformed conventionally by reaction with the appropriate acid such asdescribed above under formula (I).

The compounds of the present invention enhance acetylcholine functionvia an action at muscarinic receptors within the central nervous systemand are therefore of potential use in the treatment and/or prophylaxisof dementia.

The present invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I) or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges, suppositories, reconstitutable powders, or liquidpreparations such as oral or sterile parenteral solutions orsuspensions.

In order to obtain consistency of administration it is preferred that acomposition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulphate.

The solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

Oral liquid preparations may be in the form of, for example, emulsions,syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, or hydrogenated edible fats; emulsifying agents, forexample lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles(which may include edible oils), for example almond oil, fractionatedcoconut oil, oily esters such as esters of glycerine propylene glycol orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid; and if desired conventional flavouringor colouring agents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, and, depending on theconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, a preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, of the active material, depending on the method ofadministration.

The invention also provides a method of treatment and/or prophylaxis ofdementia in mammals including humans, which comprises administering tothe sufferer an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

The dose of the compound used in the treatment of such disorders willvary in the usual way with the seriousness of the disorders, the weightof the sufferer, and the relative efficacy of the compound. However, asa general guide suitable unit doses may be 0.05 to 250 mg, for example0.2 to 50 mg and such unit doses may be administered more than once aday, for example two or three times a day, so that the total dailydosage is in the range of about 0.01 to 50 mg/kg and such therapy mayextend for a number of weeks or months.

When administered in accordance with the invention, no unacceptabletoxicological effects are expected for the compounds of the invention.

In a further aspect the invention provides a compound of formula (I) ora pharmaceutically acceptable salt thereof for use as an activetherapeutic substance.

The invention further provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use in the treatmentand/or prophylaxis of dementia.

In another aspect the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof for thepreparation of a medicament for the treatment and/or prophylaxis ofdementia.

The following examples illustrate the invention and the followingdescriptions illustrate the preparation of intermediates thereto.

DESCRIPTION 11-Methyl-1,2,5,6-tetrahydropyridin-3-yl-N-methoxycarboxamide (D1)

Methyl (1-methyl-1,2,5,6-tetrahydropyridin-3-yl) carboxylate (1 g, 6.45mmol) and potassium hydroxide (0.83 g, 14.82 mmol) in ethanol (25 ml)were heated at reflux for 9 h. The reaction mixture was concentrated invacuo and the residue treated carefully with hydrogen chloride inmethanol until the solution was acidic. The solution was concentratedand dried under vacuum to give the carboxylic acid hydrochloride salt.Thionyl chloride (10 ml) was added and the mixture was heated at refluxunder nitrogen for 1 h. The resulting solution was concentrated in vacuoto a gum which was freed from excess thionyl chloride by co-evaporationwith toluene. The residue was dissolved in a mixture of chloroform (15ml) and dry acetonitrile (15 ml), and methoxylamine hydrochloride (0.59g, 7.07 mmol) was added. After cooling to -20° C., pyridine (2.6 ml) wasadded dropwise over 0.5 h and the reaction mixture was allowed to warmto room temperature overnight. The solvent and excess pyridine wereremoved in vacuo and the residue was partitioned between saturatedpotassium carbonate solution (50 ml) and chloroform. The aqueous layerwas further extracted with chloroform (5×50 ml) and the combined organicextracts were dried (Na₂ SO₄) and evaporated to a gum, which waschromatographed on silica using a graded eluant of 2-15%methanol/chloroform to afford the title compound (D1) (0.5 g, 38%) as anoff-white solid.

¹ H NMR (CDCl₃) δ: 2.30 (2H, m), 2.40 (3H, s), 2.53 (2H, t, J=6 Hz),3.14 (2H, m), 3.27 (3H, s), 6.45 (1H, m) .

DESCRIPTION 21-Methyl-1,2,5,6-tetrahydropyridin-3-yl-N-methoxycarboximidoyl fluoride(D2)

1-Methyl-1,2,5,6-tetrahydropyridin-3-yl-N-methoxycarboxamide (D1, 0.5 g,2.94 mmol) was converted to the hydrofluoride salt by the addition ofhydrogen fluoride-pyridine (Aldrich). The salt was dissolved inrefluxing acetonitrile (50 ml) and diethylaminosulphur trifluoride(DAST) (0.41 ml, 3.10 mmol) in acetonitrile (5 ml) was added in a singleportion. The reaction mixture was immediately cooled and poured intosaturated potassium carbonate (50 ml) and extracted with chloroform(4×50 ml). The combined organic extracts were dried (Na₂ SO₄) andevaporated to an oil which was chromatographed on silica using 0-1%methanol/chloroform as eluant to yield the title compound (D2) as an oil(0.24 g, 47%). Addition of oxalic acid and recrystallisation frommethanol/acetone afforded a colourless crystalline solid

m.p. 162°-164° C. (decomp.). Oxalate salt: ¹ H NMR (d₆ DMSO) δ: 2.54(2H, m), 2.80 (3H, s), 3.20 (2H, m), 3.74 (2H, m), 3.82 (3H, s), 6.64(1H, m). ¹³ C NMR (d₆ DMSO) δ: 22.81, 42.23, 48.67, 48.83, 63.32, 119.38(d, ² J_(CF) =26 Hz), 130.40, 147.87 (d, ¹ J_(CF) =322 Hz). MS:Calculated mass for C₈ H₁₃ N₂ OF=172.1012 Observed mass=172.1012

DESCRIPTION 3 1,2,5,6-Tetrahydropyridin-3-yl-N-methoxycarboximidoylfluoride (D3)

An ice cold solution of1-methyl-1,2,5,6-tetrahydropyridin-3-yl-N-methoxycarboximidoyl fluoride(D2) (185 mg, 1.1 mmol) in dry dichloromethane (2 ml) was treateddropwise with α-chloroethyl chloroformate (160 mg, 1.13 mmol) under anatmosphere of nitrogen. After stirring at room temperature for 4 h, thereaction mixture was concentrated in vacuo. The residue was dissolved indry methanol (4 ml) and heated under reflux for 1 h. The solution wasconcentrated in vacuo, treated with saturated aqueous potassiumcarbonate (5 ml) and extracted into chloroform (3×7 ml). The combinedorganic extracts were dried (Na₂ SO₄) and concentrated in vacuo. Theresulting gum was chromatographed on silica in a gradient of 0-3%methanol in chloroform to give the title compound (D3) as an oil (36 mg,21%).

DESCRIPTION 4 α-(Methoxyimino)-α-pyridin-3-yl)acetonitrile (D4)

Method A

Sodium metal (0.19 g, 0.0083 mol) was dissolved in dry ethanol (15 ml)at room temperature with stirring. 3-Pyridylacetonitrile (1.0 g, 0.0083mol) was added and stirred for 1 h. tert-Butyl nitrite (1.0 ml, 0.0085mol) was added and the mixture stirred for a further 1 h after whichtime a yellow precipitate had formed. Methyl iodide (1.0 ml, 0.016 mol)was added and the mixture stirred at room temperature for 2 h. Aqueouspotassium carbonate (10% solution, 50 ml) was added and the mixtureextracted with chloroform (3×100 ml). The organic layers were separatedand dried (Na₂ SO₄) then filtered and evaporated to dryness. The residuewas subjected to column chromatography on silica gel eluting withchloroform. The title compound (D4) was obtained as a colourless oilwhich crystallised on standing (0.155 g, 11%).

¹ H NMR (CDCl₃) δ: 4.25 (3H, s), 7.39-7.45 (1H, m), 8.05-8.12 (1H, m),8.61-8.75 (1H, m), 9.04 (1H, d).

Method B

To a solution of 3-pyridylacetonitrile (15 g, 0.127 mol) in drytetrahydrofuran (900 ml) at -20° C. under a nitrogen atmosphere wasadded potassium-t-butoxide (17.2 g, 0.14 mol) portionwise over 5 min.Stirring was continued at this temperature for 1 h. t-Butylnitrite (16.6ml, 0.14 mol) was then added and the mixture allowed to warm to roomtemperature. The mixture was stirred for a further 2 h then methyliodide (10.5 ml, 0.168 mol) was added. The mixture was stirred for afurther 20 h and then concentrated in vacuo. The residue was partitionedbetween 10% aqueous potassium carbonate solution and ethyl acetate. Theorganics were separated and dried (Na₂ SO₄) and evaporated to dryness.The residue was subjected to column chromatography on silica gel elutingwith 0-1% methanol/chloroform. This gave the title compound (D4) as anoil (17.6 g, 86%).

DESCRIPTION 5 α-(Methoxyimino)-α-(1-oxopyridinium-3-yl)acetonitrile (D5)

α-(Methoxyimino)-α-(1-pyridin-3-yl)acetonitrile (D4) (0.72 g, 0.0045mol) was dissolved in dry dichloromethane (50 ml) and cooled to 0° C.m-Chloroperoxybenzoic acid (85% purity) (1.0 g, 0.0049 mol) was addedwith stirring. After 2 h a further amount of m-chloroperoxybenzoic acid(0.5 g, 0.0025 mol) was added and the mixture stirred for another 2 h.Aqueous potassium carbonate (10% solution, 100 ml) was added and themixture extracted with chloroform (2×100 ml). The combined organicextracts were dried (Na₂ SO₄), filtered and evaporated to dryness togive the title compound (D5) as a yellow crystalline solid (0.69 g,87%).

¹ H NMR (CDCl₃) δ: 4.27 (3H, s), 7.38 (1H, t, J=6 Hz), 7.62 (1H, d, J=8Hz), 8.29 (1H, d, J=6 Hz), 8.67 (1H, s).

DESCRIPTION 6 α-(Methoxyimino)-α-(1-methylpyridinium-3-yl)acetonitrileiodide (D6)

α-(Methoxyimino)-α-(pyridin-3-yl)acetonitrile (D4) (0.155 g, 0.00096mol) was heated under reflux with methyl iodide (5 ml) in methanol (5ml) for 60 h. The mixture was evaporated to dryness to give the titlecompound (D6) (0.3 g, 100%) which was used without further purification.

DESCRIPTION 7α-(Methoxyimino)-α-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile(D7)

α-(Methoxyimino)-α-(1-methylpyridinium-3-yl)acetonitrile iodide (D6)(0.3 g, 0.001 mol) was dissolved in methanol (10 ml) and cooled to 0° C.Sodium borohydride (0.114 g, 0.003 mol) was added in three equalportions at 15 minute intervals. The mixture was allowed to warm to roomtemperature over 1 h and then evaporated to dryness. The residue waspartitioned between saturated aqueous potassium carbonate solution (50ml) and chloroform (3×75 ml). The organic layers were separated anddried (Na₂ SO₄) then filtered and evaporated to dryness. The residue wassubjected to column chromatography on silica gel eluting with 0-1%methanol/chloroform. This gave the title compound (D7) as an oil (0.04g, 23%). A portion of this material was converted to the oxalate saltand crystallised from ethanol/diethyl ether to give a white crystallinesolid m.p. 157°-158° C.

Free base ¹ H NMR (CDCl₃) δ: 2.40 (3H, s), 2.40-2.49 (2H, m), 2.53-2.61(2H, m), 3.13-3.20 (2H, m), 4.07 (3H, s), 6.50-6.55 (1H, m). MSCalculated for C₉ H₁₃ N₃ O=179.1058 Observed mass=179.1057 Analysis(oxalate) C₁₁ H₁₅ N₃ O₅ requires C:49.07; H:5.62; N:15.61; foundC:49.17; H:5.72; N:15.59.

DESCRIPTION 8α-(Methoxyimino)-α-(1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (D8)

α-(Methoxyimino)-α-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile(D7) (0. 047 g, 0.00026 moles) was dissolved in dry dichloromethane (1ml) and cooled to 0° C. under a nitrogen atmosphere. α-Chloroethylchloroformate (0.041 g, 0.00029 moles) was added with stirring and themixture allowed to warm to room temperature. The mixture was stirred fora further 4 h and then evaporated to dryness. Methanol (5 ml) was addedand the mixture was heated under reflux for 1 h. Evaporation of thesolvent gave an oil which was partitioned between saturated aqueouspotassium carbonate and chloroform. The organic phase was separated anddried (Na₂ SO₄) then evaporated to dryness. Column chromatography onsilica-gel eluting with 0-2% methanol/chloroform gave the title compound(D8) as a crystallising oil (0.03 g, 69%). Treatment with anhydrousoxalic acid afforded a white crystalline solid m.p. 180°-190° C.

Oxalate salt: ¹ H NMR (d₆ -DMSO) δ: 2.45-2.57 (2H, m), 3.12-3.21 (2H,m), 3.76 (2H, s), 4.08 (3H, s), 6.58-6.63 (1H, m), 7.00-8.30 (2H, br s).Analysis C₈ H₁₁ N₃ O.C₂ H₂ O₄ requires C: 47.06; H: 5.13; N: 16.46;found C: 46.95; H: 5.14; N: 16.25.

DESCRIPTION 91-Methyl-1,2,5,6-tetrahydropyridin-3-yl)-N-methoxycarboximidoyl chloride(D9)

Triphenylphosphine (3.24 g, 12.37 mmol) was added in a single portion to1-methyl-1,2,5,6-tetrahydropyridin-3-yl-N-methoxycarboxamide (D1, 2 g,11.76 mmol) in acetonitrite (200 ml) and carbon tetrachloride (5 ml) atreflux. The mixture was heated under reflux for 0.5 h, cooled, thenpoured into saturated aqueous potassium carbonate solution (100 ml) andextracted with chloroform (4×100 ml). The combined extracts were washedwith 1M hydrochloric acid (2×100 ml). The combined acid extracts werethen basified and saturated with potassium carbonate and extracted withchloroform (4×150 ml). The organic extracts were dried (Na₂ SO₄) andevaporated to an oil which was chromatographed on silica using ether aseluant to give the title compound (D9) as an oil (1.03 g, 46%). Aportion of this material was converted to the oxalate salt andrecrystallised from methanol/acetone to give a colourless solid m.p.166° C. (decomp.).

Oxalate: ¹ H NMR (d₆ DMSO) δ: 2.56 (2H, m), 2.78 (3H, s), 3.16 (2H, t,J=6 Hz), 3.82 (2H, m), 3.98 (3H, s), 6.73 (1H, m). ¹³ C NMR (d₆ -DMSO)δ: 23.33, 42.59, 49.06, 51.10, 62.82, 125.93, 134.94, 163.11. Analysis:C₈ H₁₃ N₂ OCl.C₂ H₂ O₄ requires C: 43.1; H: 5.43; N: 10.05; found C:43.06; H: 5.39; N: 9.98.

DESCRIPTION 10 1,2,5,6-Tetrahydropyridin-3-yl-N-methoxycarboximidoylchloride (D10)

1-Methyl-1,2,5,6-tetrahydropyridin-3-yl-N-methoxycarboximidoyl chloride(D9) (2.0 g, 0.01 moles) was treated with α-chloroethyl chloroformate asin the method of Description 3. This gave the title compound (D10) as acrystallising oil (0.99 g, 53%). A small amount was treated withanhydrous oxalic acid and the resulting oxalate salt was recrystallisedfrom ethanol/diethyl ether to give a white crystalline solid m.p.183°-5° C.

Oxalate: ¹ H NMR (d₆ -DMSO) δ: 2.52-2.65 (2H, m), 3.25-3.31 (2H, m),3.86-3.94 (2H, m), 4.07 (3H, s), 3.40-4.50 (3H, br s), 6.83 (1H, m).Analysis C₇ H₁₁ N₂ OCl.C₂ H₂ O₄ requires C:40.83; H:4.91; N:10.59; foundC:40.62; H:4.90; N:10.35.

EXAMPLE 11,2,5,6-Tetrahydro-1-(4-methoxyphenyloxycarbonyl)pyridin-3-yl-N-methoxycarboximidoylfluoride (E1)

An ice cold solution of1,2,5,6-tetrahydropyridin-3-yl-N-methoxycarboximidoyl fluoride (D3) (50mg, 0.32 mmol) in dry toluene (5 ml) containing dry triethylamine (35mg, 0.35mmol) was treated dropwise with 4-methoxyphenyl chloroformate(65 mg, 0.35 mmol), under an atmosphere of nitrogen. After stirring atroom temperature for 40 min the solution was diluted with chloroform (50ml) and washed with dilute hydrochloric acid (50 ml), dried (Na₂ SO₄)then concentrated in vacuo. The residue was chromatographed on neutralalumina in a gradient of 5-10% ethyl acetate in cyclohexane to give asolid which was recrystallised from hexane to afford the title compound(E1) as a white solid (70 mg, 72%) m.p. 91°-93° C.

¹ H NMR (d₆ -DMSO, 80° C.) δ: 2.39-2.44 (2H, m), 3.60-3.68 (2H, m), 3.78(3H, s), 3.85 (3H, s), 4.13-4.18 (2H, m), 6.62-6.66 (1H, m), 6.91-6.96(2H, m), 7.05-7.10 (2H, m) Analysis C₁₅ H₁₇ FN₂ O₄ requires C: 58.44; H:5.56; N: 9.09; found C: 58.49; H: 5.56; N: 9.24.

EXAMPLE 2α-(Methoxyimino)-α-(1-hydroxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile(E2)

Sodium borohydride (0.13 g, 0.0034 mol) was added to a mixture ofmethanol (5 ml) and water (5 ml) at 0° C. To this was added dropwise asolution of α-(methoxyimino)-α-(1-oxopyridinium-3-yl)acetonitrile (D5)(0.2 g, 0.0011 mol) in methanol (30 ml) and water (5 ml). The mixturewas allowed to warm to room temperature and stirred for a further 2 h.The mixture was evaporated to dryness and the residue partitionedbetween saturated aqueous potassium carbonate (25 ml) andchloroform(3×30 ml). The organic extracts were combined and dried (Na₂SO₄) then filtered and evaporated to dryness. The residue was subjectedto column chromatography on silica gel eluting with 0-2%methanol/chloroform to give a solid which was recrystallised from ethylacetate/pentane to afford the title compound (E2) as a white crystallinesolid (0.135 g, 67%) m.p. 145°-147° C.

¹ H NMR (CDCl₃) δ: 2.42-2.59 (2H, m), 2.90-3.03 (1H, m), 3.10-3.26 (1H,m), 3.35-3.52 (1H, m), 3.83-3.95 (1H, m), 4.08 (3H, s), 6.47-6.51 (1H,m). Analysis C₈ H₁₁ N₃ O₂ requires C: 53.03; H: 6.12; N: 23.19; found:C: 53.27; H: 6.19; N: 23.10.

EXAMPLE 3α-(Methoxyimino)-α-[1,2,5,6-tetrahydro-1-(phenyloxycarbonyl)pyridin-3-yl]acetonitrile(E3)

α-(Methoxyimino)-α-(1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (D8)(0.5 g, 0.003 moles) was treated with phenyl chloroformate (0.42 ml,0.0033 moles) according to the method of Example 1. The crude productwas crystallised from diethyl ether/pentane to give the title compound(E3) as a white crystalline solid (0.7 g, 81%) m.p. 111°-112° C.

¹ H NMR (CDCl₃) δ: 2.42-2.58 (2H, br s), 3.63-3.80 (2H, m), 4.10 (3H,s), 4.27-4.41 (2H, m), 6.60-6.73 (1H, br s), 7.05-7.41 (5H, m). AnalysisC₁₅ H₁₅ N₃ O₃ requires C: 63.15; H: 5.30; N: 14.73; found C: 63.31; H:5.30; N: 14.70.

EXAMPLE 4α-(Methoxyimino)-α-[1,2,5,6-tetrahydro-1-(4-methoxyphenyloxycarbonyl)pyridin-3-yl]acetonitrile(E4)

α-(Methoxyimino)-α-(1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (D8)(0.5 g, 0.003 moles) was treated with 4-methoxyphenylchloroformate (0.5ml, 0.0033 moles) as in the method of Example 1. The crude produce wastriturated with pentane to give the title compound (E4) as a whitecrystalline solid (0.81 g, 85%) m.p. 75°-76° C.

¹ H NMR (CDCl₃) δ: 2.42-2.53 (2H, br s), 3.14-3.79 (2H, m), 3.80 (3H,s), 4.10 (3H, s), 4.25-4.39 (2H, m), 6.60-6.71 (1H, br s), 6.87 (2H, d,J=11 Hz), 7.03 (2H, d, J=11 Hz) Analysis C₁₆ H₁₇ N₃ O₄ requires C:60.94; H: 5.43; N: 13.33; found C: 60.94; H: 5.35; N: 13.10.

EXAMPLE 5α-(Methoxyimino)-α-[1,2,5,6-tetrahydro-1-(3,4-dimethoxyphenyloxycarbonyl)pyridin-3-yl]acetonitrile(E5)

α-(Methoxyimino)-α-[1,2,5,6-tetrahydropyridin-3-yl]acetonitrile (D8)(0.5 g, 0.003 moles) was treated with 3,4-dimethoxyphenylchloroformate*(0.67 g, 0.0031 moles) as in the method of Example 1. The crude productwas crystallised from diethyl ether/hexane to give the title compound(E5) as a white crystalline solid (0.65 g, 62%) m.p. 99°-100° C.

¹ H NMR (CDCl₃) δ: 2.45-2.55 (2H, br s), 3.65-3.80 (2H, m), 3.85 (6H,s), 4.10 (3H, s), 4.27-4.41 (2H, m), 6.61-6.72 (3H, m), 6.84 (1 h, d,J=12 Hz). Analysis C₁₇ H₁₉ N₃ O₅ requires C: 59.12; H: 5.55; N: 12.17;found C: 59.33; H: 5.58; N: 12.07.

EXAMPLE 61-Hydroxy-1,2,5,6-tetrahydropyridin-3-yl-N-methoxycarboximidoyl chloridehydrochloride salt (E6)

1,2,5,6-Tetrahydropyridin-3-yl-N-methoxycarboximidoyl chloride (D10)(0.5 g, 0.0028 moles) was dissolved in tetrahydrofuran (50 ml) andtreated with disodium hydrogen phosphate (2.03 g, 0.014 moles) followedby benzoyl peroxide (1.1 g, 70% pure; 0.0031 moles) with stirring. Themixture was kept at ambient temperature for 60 hrs and then filtered.The filtrate was evaporated to dryness and the residue partitionedbetween saturated sodium bicarbonate solution and ethyl acetate. Theorganic layer was collected and dried (Na₂ SO₄), filtered and evaporatedto dryness. The residue was purified by flash chromatography on TLCsilica gel eluting with 5% ethyl acetate in 60-80 petrol. This gave theN-benzoyloxy compound (0.26 g) which was dissolved in dry diethyl ether(10 ml) and methanol (2 ml) and treated with sodium methoxide (3.48molar solution in methanol; 0.29 ml, 0.001 moles). The mixture wasstirred at ambient temperature for 30 mins. Water (10 ml) was added andthe resulting mixture extracted with diethyl ether (2×50 ml). Theorganics were separated, dried (Na₂ SO₄), filtered and evaporated todryness. The residue was dissolved in ethanol (1 ml) and treated with 1Mhydrogen chloride in diethyl ether to give a crystalline solid.Recrystallisation from acetone/diethyl ether gave the title compound(E6) as a white crystalline solid (0.05 g, 9%) m.p. 135°-7° C.

¹ H NMR (d₆ -dMSO) δ: 2.56-2.72 (2H, m), 3.30-3.60 (2H, m), 3.95 (1H, d,J=20 Hz), 3.99 (3H, s), 4.25 (1H, d, J=20 Hz), 6.68-6.75 (1H, m), 11.63(1H, br s). Analysis C₇ H₁₁ ClN₂ O₂.HCl requires C: 37.02; H:5.33;N:12.34; found C:36.83; H:5.32; N:11.96.

EXAMPLE 71,2,5,6-Tetrahydro-1-(4-methoxyphenyloxycarbonyl)pyridin-3-yl-N-methoxycarboximidoylchloride (E7)

1,2,5,6-Tetrahydropyridin-3-yl-N-methoxycarboximidoyl chloride (D10)(0.106 g, 0.0006 moles) was treated with 4-methoxyphenylchloroformate asin the method of Example 1. The residue obtained was chromatographed onsilica-gel eluting with 0-1% methanol in chloroform to give a gum whichcrystallised from ethyl acetate/pentane to give the title compound (E7)(0.11 g, 56%) m.p. 103°-5° C.

¹ H NMR (CDCl₃) δ: 2.35-2.48 (2H, m), 3.61-3.78 (2H, m), 3.80 (3H, s),4.02 (3H, s), 4.30-4.47 (2H, m), 6.65-6.67 (1H, m), 6.85 (2H, d, J=10Hz), 7.02 (2H, d, J=10 Hz). Analysis C₁₅ H₁₇ ClN₂ O₄ requires C:55.48;H:5.28; N:8.63; found C:55.38; H:5.29; N:8.55.

EXAMPLE 8α-(Methoxyimino)-α-(1-propylaminocarbonyloxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile(E8)

Propyl isocyanate (0.23 g, 0.00275 moles) was added to a solution ofα-(methoxyimino)-α-(1-hydroxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile(E2) (0.45 g, 0.0025 moles ) in dry toluene (20 ml) with stirring. Themixture was kept at ambient temperature for 2 hrs then evaporated todryness. The resulting residue crystallised from ethyl acetate/60-80petrol. Recrystallisation from the same solvent system gave the titlecompound (E8) as a white crystalline solid (0.37 g, 56%) m.p. 95°-6° C.

¹ H NMR (CDCl₃) δ: 0.95 (3H, t, J=7 Hz), 1.49-1.63 (2H, m), 2.45-2.68(2H, m), 3.17-3.27 (4H, m), 3.68-3.75 (1H, brs), 3.85-3.95 (1H, brs),4.10 (3H, s), 6.50-6.60 (2H, m). Analysis C₁₂ H₁₈ N₄ O₃ requiresC:54.12; H:6.81; N:21.04; found C:54.03; H:6.75; N:20.99.

EXAMPLE 9α-(Methoxyimino)-α-(1-phenylaminocarbonyloxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile(E9)

α-(Methoxyimino)-α-(1-hydroxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile(E2) (0.45 g, 0.0025 moles) was treated with phenyl isocyanate as in themethod of Example 8. The residue obtained was chromatographed on silicagel eluting with 0-1% methanol/chloroform to give a crystalline solid.Recrystallisation from ethyl acetate/60-80 petrol gave the titlecompound (E9) as white crystals (0.245 g, 33%) m.p. 128°-130° C.

¹ H NMR (CDCl₃) δ: 2.45-2.75 (2H, m), 3.27-3.37 (2H, m), 3.75-4.03 (2H,m), 4.08 (3H, s), 6.58-6.63 (1H, m), 7.12 (1H, t, J=7 Hz ), 7.32 (2H, t,J=7 Hz), 7.47 (2H, d, J=10 Hz), 8.45-8.52 (1H, br s). Analysis C₁₅ H₁₆N₄ O₃ requires C:59.99; H:5,37; N:18.66; found C:60.10; H:5.42; N:18.69.

EXAMPLE 10α-(Methoxyimino)-α-(1-acetoxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile(E10)

α-(Methoxyimino)-α-(1-hydroxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile(E2) (0.5 g, 0.0028 moles) was dissolved in dry tetrahydrofuran (20 ml)and treated with triethylamine (0.43 ml, 0.0031 moles) with stirring atroom temperature. This mixture was then treated with acetyl chloride(0.22 ml, 0.0031 moles) and stirred at ambient temperature for 2 h. Themixture was filtered and the filtrate evaporated to dryness. The residuewas chromatographed on silica gel eluting with chloroform. Thecrystalline residue was recrystallised from 60-80 petrol to give thetitle compound (E10) as an off-white crystalline solid (0.234 g, 38%)m.p. 87°-8° C.

¹ H NMR (CDCl₃) δ: 2.07 (3H, s), 2.49-2.60 (2H, m), 3.19-3.28 (2H, m),3.60-4.05 (2H, br s), 4.07 (3H, s), 6.52-6.59 (1H, m). Analysis C₁₀ H₁₃N₃ O₃ requires C:53.81; H:5.87; N:18.82; found C:54.02; H:5.91; N:18.82.

    ______________________________________                                        Compound   R.sub.10        R.sub.2  R.sub.3                                   ______________________________________                                        E1         4-Methoxyphenyloxy-                                                                           OCH.sub.3                                                                              F                                                    carbonyl                                                           E2         OH              OCH.sub.3                                                                              CN                                        E3         Phenyloxycarbonyl                                                                             OCH.sub.3                                                                              CN                                        E4         4-Methoxyphenyloxy-                                                                           OCH.sub.3                                                                              CN                                                   carbonyl                                                           E5         3,4-Dimethoxy-  OCH.sub.3                                                                              CN                                                   phenyloxycarbonyl                                                  E6         OH              OCH.sub.3                                                                              Cl                                        E7         4-Methoxyphenyloxy-                                                                           OCH.sub.3                                                                              Cl                                                   carbonyl                                                           E8         Propylamino-    OCH.sub.3                                                                              CN                                                   carbonyloxy                                                        E9         Phenylamino     OCH.sub.3                                                                              CN                                                   carbonyloxy                                                         E10       Acetoxy         OCH.sub.3                                                                              CN                                        ______________________________________                                    

Biological Activity

Determination of central muscarinic activity

Male mice (CD1, Charles River) weighing 25-35 g are used. Bodytemperature is measured using an electronic thermometer with a rectalprobe.

At 30 minutes predose, atropine methyl nitrate (0.3 mgkg-¹ sc) isadministered in order to block peripheral effects of the compound understudy. Test compound is administered subcutaneously at time (t)=O andbody temperature is recorded at t=O, 15, 30, 45, 60, 90 and 120 minutespost dose. The dose which induces a 3° C. drop in body temperaturecompared to control is noted. Duration of action of the test compound iscalculated as the time taken for the hypothermic response of 3° C. to bereduced by half (i.e. to 1.5° C).

    ______________________________________                                                      Effective dose                                                                            Duration                                            Compound      (-3° C.) mg/kg                                                                     min                                                 ______________________________________                                        2             2.0          90                                                 4             0.9         180                                                 5             0.6         180                                                 ______________________________________                                    

We claim:
 1. A compound of Formula (I) or a pharmaceutically acceptablesalt thereof: ##STR10## wherein R₁ represents a1,2,5,6-tetrahydropyridin-3-yl group N-substituted by R₁₀ wherein R₁₀represents OH; C₁₋₈ alkanoyloxy, C₁₋₈ alkoxycarbonyloxy, phenyl C₁₋₄alkanoyloxy and --OCONHR₁₂ wherein R₁₂ is hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, phenyl or phenyl C₁₋₄ alkyl, orR₁₀ is COOZ in which Z represents C₁₋₁₈ alkyl optionally substituted bytri C₁₋₆ alkylsilyl or C₁₋₆ alkylsulphonyl, C₂₋₁₈ alkenyl, C₂₋₁₈alkynyl, C₃₋₈ cycloalkyl C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, phenyl or phenylC₁₋₄ alkyl; C₁₋₈ alkoxy; C₂₋₈ alkenyloxy; C₂₋₈ alkynyloxy; C₃₋₈cycloalkyloxy; or COR₁₃ wherein R₁₃ represents hydrogen, C₁₋₈ alkyl,phenyl or phenyl C₁₋₄ alkyl; any of the above phenyl moieties isoptionally substituted by up to 3 substituents independently selectedfrom C₁₋₆ alkoxy, C₁₋₆ alkyl, halo, C₁₋₆ alkoxycarbonyl, cyano, C₁₋₆alkylthio or C₁₋₆ alkylsulphonyl; R₂ is a group OR₄ where R₄ is C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a group OCOR₅ where R₅ is hydrogen orR₄, or a group NHR₆ or NR₇ R₈ where R₆, R₇ and R₈ are independently C₁₋₂alkyl; and R₃ is chloro, fluoro, bromo, C₁₋₃ alkyl substituted by one,two or three halogen atoms, or R₃ is a group (CH₂)_(n) R₉ where R₉ is--CN, --OH, --OCH₃, --SH or SCH₃ and n is O or 1, with the provisio thatwhen n is O, R₉ is not --OH or --SH.
 2. A compound according to claim 1wherein R₁₀ is selected from hydroxy, phenyloxycarbonyl,4-methoxyphenyloxycarbonyl, 3,4-dimethoxyphenyloxycarbonyl, acetoxy,propylaminocarbonyloxy and phenylaminocarbonyloxy.
 3. A compoundaccording to claim 1 wherein R₄ and R₅ in R₂ are selected from methyl,ethyl, allyl and propargyl and R₆, R₇ and R₈ in R₂ are methyl.
 4. Acompound according to claim 1 where R₃ is selected from methoxy, chloro,fluoro, bromo, CN and CH₂ CN.
 5. A compound according to claim 1selected from the group consistingof:1,2,5,6-tetrahydro-1-(4-methoxyphenyloxycarbonyl)-pyridin-3-yl-N-methoxycarboximidoylfluoride;α-(methoxyimino)-α-(1-hydroxy-1,2,5,6-tetrahydro-pyridin-3-yl)acetonitrile;α-(methoxyimino)-α-[1,2,5,6-tetrahydro-1-(phenyloxy-carbonyl)pyridin-3-yl]acetonitrile;α-(methoxyimino)-α-[1,2,5,6-tetrahydro-1-(4-methoxy-phenyloxycarbonyl)pyridin-3-yl]acetonitrile;α-(methoxyimino)-α-[1,2,5,6-tetrahydro-1-(3,4-dimethoxyphenyloxycarbonyl)pyridin-3-yl]acetonitrile;1-hydroxy-1,2,5,6-tetrahydropyridin-3-yl-N-methoxycarboximidoylchloride;1,2,5,6-tetrahydro-1-(4-methoxyphenyloxycarbonyl)-pyridin-3-yl-N-methoxycarboximidoylchloride;α-(methoxyimino)-α-(1-propylaminocarbonyloxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile;α-(methoxyimino)-α-(1-phenylaminocarbonyloxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile;andα-(methoxyimino)-α-(1-acetoxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile,or a a pharmaceutically acceptable salt of any of the foregoingcompounds.
 6. A method of treatment of dementia in mammals, whichcomprises administering to the sufferer an effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof.